Alcoholic liver disease is a major cause of chronic liver disease worldwide. The spectrum of alcoholic liver disease includes simple steatosis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. In patients with underlying alcoholic liver disease and heavy alcohol intake, episodes of superimposed acute alcoholic hepatitis (AH) may occur. In severe cases, AH leads to severe complications related to liver failure and portal hypertension and has high short-term mortality. Despite the profound economic and health impact of AH, little progress has been made in the management of patients with this severe clinical conditions; and no new drugs for alcoholic hepatitis have been successfully developed since the early 1970s, at which time the use of corticosteroids was proposed for the treatment of severe AH.
In 1951, Soderstrom noted that patients suffering from severe liver disease, when treated with choline, spread an unpleasant odor and that their urine had a very disagreeable smell. A sample of such urine was sent for chemical analysis and TMA was actually isolated. In agreement with this finding, Mitchell et al examined the urine of 63 patients with various liver diseases. In total, 50% of the patients had urinary TMA levels greater than the upper end of the range considered normal (0.08-1.84 microg/ml). Seventeen patients excreted large amounts of free TMA in the urine (>10 microg/ml), above the threshold usually associated with the appearance of a ‘fish-like’ body odor and tainted breath—traditionally known as fetor hepaticus.
To date, the diagnosis of AH is made clinically based on a typical presentation, with severe liver dysfunction in the context of excessive alcohol consumption, and the exclusion of other causes of acute and chronic liver disease. However, it has been shown that the physician's clinical impression may correlate only moderately well with the diagnosis of AH. Studies that have included a liver biopsy in all patients with clinically diagnosed AH have shown histological confirmation in only 70%-80% of patients. Therefore, in the absence of non-invasive alternatives, liver biopsy remains today the gold standard for the diagnosis of acute AH. However, liver biopsy is an invasive procedure, and it carries a risk of complications. Indeed, 1% to 5% of patients require hospitalization after the procedure. Furthermore, sampling error and interobserver variability add to the limitations of liver biopsy. Therefore, there is an increasing demand for alternative noninvasive methods for the diagnosis of AH.
The clinical use of breath as a medical tool in the diagnosis of chronic liver disease has been reported many years ago in the description of fetor hepaticus “a distinctive musty, sweet breath odor in individuals with severe liver disease”. With recent advances in technology, it is possible to identify thousands of substances in the breath, such as volatile compounds and elemental gases. Using selected-ion flow-tube mass spectrometry (SIFT-MS), precise identification of trace gases in the human breath in the parts per trillion ranges can be achieved.
A recent study by Wang et al., (Nature, 2011 Apr. 7; 772(7341): 57-63), has identified a novel pathway linking dietary lipid intake, intestinal microflora and atherosclerosis. Researchers showed that intestinal microflora plays an important role in the formation of trimethylamine (TMA) from dietary phosphatidylcholine and dietary free choline shown in FIG. 1. Hepatic flavin monooxygenase (FMO) family of enzymes, FMO3 convert TMA, a volatile organic compound which smells like rotting fish, into trimethylamine N-oxide (TMAO), an odorless stable oxidation product which contributes to the atherosclerosis in humans. Subjects with chronic liver disease, in general, have impaired capacity to convert TMA into TMAO. Furthermore, alcohol consumption in patients with alcoholic liver disease induces bacterial overgrowth and increases gut permeability and the translocation of bacteria-derived lipopolysaccharides from the gut to the liver. It therefore may be desirable to determine whether the amounts or concentration of volatile compounds in a biological sample, for example, a breath sample correlate with the diagnosis of liver disease.